Publications

OBJECTIVE

We investigated potential interactions between human leukocyte antigen (HLA) genotype and body mass index (BMI) status in relation to the risk of developing multiple sclerosis (MS).

METHODS

We used 2 case-control studies, one with incident cases (1,510 cases, 2,017 controls) and one with prevalent cases (937 cases, 609 controls). Subjects with different genotypes and BMI were compared with regard to incidence of MS by calculating odds ratios (ORs) with 95% confidence intervals (CIs) employing logistic regression. Potential interactions between genotypes and BMI were evaluated by calculating the attributable proportion due to interaction.

RESULTS

In both cohorts, a significant interaction was observed between HLA-DRB1*15 and obesity, regardless of HLA-A*02 status. Similarly, there was a significant interaction between absence of A*02 and obesity, regardless of DRB1*15 status. In the incident cohort, obese subjects with the most susceptible genotype (carriage of DRB1*15 and absence of A*02) had an OR of 16.2 (95% CI 7.5-35.2) compared to nonobese subjects without the genetic risk factors. The corresponding OR in the prevalent study was 13.8 (95% CI 4.1-46.8).

CONCLUSIONS

We observed striking interactions between BMI status and HLA genotype with regard to MS risk. Hypothetically, a low-grade inflammatory response inherent to obesity synergizes with the adaptive, HLA molecule-restricted arm of the immune system, causing MS. Prevention of adolescent obesity may thus lower the risk of developing MS, predominantly among people with a genetic susceptibility to the disease.

Heart failure (HF) and atrial fibrillation (AF) commonly coexist and adversely affect mortality when found together. AF begets HF and HF begets AF. Rhythm restoration with antiarrhythmic drugs failed to show a mortality benefit but can be effective in improving symptoms. Nonpharmacologic treatment of AF may be of value in the HF population.

Emerging evidence indicates that myeloid cells are essential for promoting new blood vessel formation by secreting various angiogenic factors. Given that hypoxia-inducible factor (HIF) is a critical regulator for angiogenesis, we questioned whether HIF in myeloid cells also plays a role in promoting angiogenesis. To address this question, we generated a unique strain of myeloid-specific knockout mice targeting HIF pathways using human S100A8 as a myeloid-specific promoter. We observed that mutant mice where HIF-1 is transcriptionally activated in myeloid cells (by deletion of the von Hippel-Lindau gene) resulted in erythema, enhanced neovascularization in matrigel plugs, and increased production of vascular endothelial growth factor (VEGF) in the bone marrow, all of which were completely abrogated by either genetic or pharmacological inactivation of HIF-1. We further found that monocytes were the major effector producing VEGF and S100A8 proteins driving neovascularization in matrigel. Moreover, by using a mouse model of hindlimb ischemia we observed significantly improved blood flow in mice intramuscularly injected with HIF-1-activated monocytes. This study therefore demonstrates that HIF-1 activation in myeloid cells promotes angiogenesis through VEGF and S100A8 and that this may become an attractive therapeutic strategy to treat diseases with vascular defects.